European and US regulators approve AbbVie's new combo for all hepatitis C genotypes

The European Commission and the US Food and Drug Administration (FDA) last week approved AbbVie's new combination pill for people with hepatitis C virus (HCV) genotypes 1 to 6, to be marketed as Maviret in the European Union and as Mavyret in the United States.

Maviret is a fixed-dose co-formulation containing the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir; both drugs are being approved for the first time.

"Maviret is an 8-week, pan-genotypic treatment for non-cirrhotic patients new to treatment with chronic hepatitis C that met all primary efficacy endpoints in its extensive HCV clinical trial program, achieving high cure rates," said Prof Stefan Zeuzem of J.W. Goethe University Hospital in Frankfurt, one of the glecaprevir/pibrentasvir trial investigators. "Maviret offers a new therapy for the majority of HCV patients and removes many complexities of pre-treatment patient evaluation."

Maviret is indicated for previously untreated people, or those treated with prior interferon-based therapy, who have HCV genotypes 1, 2, 3, 4, 5 or 6 and who either do not have liver cirrhosis or have compensated cirrhosis (Child-Pugh class A). Pangenotypic regimens that work against all genotypes have the potential to be used anywhere in the world without the need for prior genotypic testing.

Treatment with Maviret requires three combination pills taken together once daily with food. The recommended treatment duration may be 8, 12 or 16, depending on various factors. For previously untreated people, treatment duration is 8 weeks for those without cirrhosis and 12 weeks for those with compensated cirrhosis.

In the European indication, Maviret is not recommended for retreatment of people who previously used NS3A/4A protease inhibitors or NS5A polymerase inhibitors. In the US indication, it is approved for adults with HCV genotype 1 who were previously treated with either an NS3/4A inhibitor or an NS5A inhibitor, but not both.

The new therapy was approved based on clinical trials showing that it leads to high rates of sustained virological response, or continued undetectable HCV at 12 weeks post-treatment (SVR12), which is considered a cure. AbbVie's application for approval was supported by data from nine registrational trials that tested glecaprevir/pibrentasvir in approximately 2300 people with or without compensated cirrhosis in 27 countries, according to the company.

In the Phase 3 ENDURANCE trials, glecaprevir/pibrentasvir taken for 8 or 12 weeks cured 98 to 100% of treatment-naive and treatment-experienced people without cirrhosis with HCV genotypes 1, 2, 4, 5 and 6.

In ENDURANCE-3, the combo taken for either 8 or 12 weeks cured 95% of people with HCV genotype 3 and cirrhosis – considered one of the most difficult groups to treat.

Results presented at this year's EASL International Liver Congress showed that glecaprevir/pibrentasvir is highly effective in people with cirrhosis. In the EXPEDITION-1 study 99% of people with HCV genotypes 1, 2, 4, 5 and 6 who had early cirrhosis achieved SVR12 with 12 weeks of therapy.

As reported at last month's IAS Conference on HIV Science, glecaprevir/pibrentasvir cured 98% of people with HIV/HIV co-infection in the EXPEDITION-2 trial. In addition, the combo was highly effective for people with hepatitis C with chronic kidney disease, including those on dialysis, in EXPEDITION-4.

Glecaprevir/pibrentasvir was generally safe and well tolerated in clinical trials, with few serious drug-related adverse events or drug discontinuations for this reason. The most common adverse events associated with the combination were headache, fatigue, nausea and diarrhoea, which in most cases were mild.

Maviret is not recommended for people with significant liver function impairment (Child-Pugh class B), and it is contraindicated for those with decompensated cirrhosis (Child-Pugh class C). The drugs in Maviret can interact with several other medications, which could lead to subtherapeutic drug levels or more intense side-effects. It should not be used with the HIV protease inhibitor atazanavir (Reyataz) or the tuberculosis medication rifampicin. It is not recommended with a number of other medications including darunavir (Prezista), lopinavir/ritonavir (Kaletra), efavirenz (Sustiva), the anti-seizure drug carbamazepine or St John’s wort. 

As is the case with all direct-acting antivirals, curing hepatitis C can trigger hepatitis B virus (HBV) reactivation, which can lead to severe liver injury. Anyone considering treatment with Maviret should be screened for HBV, and those with active HBV should receive hepatitis B antiviral therapy.